Scapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy type IIC (HMSN IIC) or Charcot-Marie-Tooth disease type 2C (CMT2C) are phenotypically heterogeneous disorders involving topographically distinct nerves and muscles. Scapuloperoneal syndromes can resemble facioscapulohumeral muscular dystrophy (FSH) due to scapular weakness or HMSN (or CMT) due to atrophy of peroneal muscles. In a large New England kindred of French-Canadian origin, Delong and Siddique identified 20 individuals in five generations affected with a neurogenic scapuloperoneal amyotrophy (DeLong and Siddique, 1992; herein incorporated by reference in its entirety). The disease is transmitted as an autosomal dominant trait and is characterized by congenital absence of muscles, developmental abnormalities of the bones, progressive scapuloperoneal atrophy and weakness, and laryngeal palsy eventually requiring permanent tracheostomy. On account of the distinct topographical distribution of muscle weakness and atrophy, it was considered a form of scapuloperoneal spinal muscular atrophy (SPSMA) (DeLong and Siddique, 1992; herein incorporated by reference in its entirety). Using genetic linkage analysis of this kindred, Isozumi et al. and mapped the SPSMA locus to chromosome 12q24.1-q24.31 within a 14 Mb interval between D12S338 and D12S366, with a two-point lod score of 6.67 and multipoint lod scores of 7.38 (Isozumi et al., 1996; herein incorporated by reference in its entirety).
HMSN or CMT is the most common inherited peripheral neuropathy. It includes a group of clinically and genetically heterogeneous hereditary neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, and depressed or absent tendon reflexes. It can be categorized according to its clinical, electrophysiological or pathological features, transmission patterns, age of disease onset, and molecular pathology. It may appear as HMSN if muscle weakness is predominant with mild sensory deficits; distal hereditary motor neuropathy (dHMN) if the motor deficit is dominant; and hereditary sensory neuropathy (HSN) or hereditary sensory and autonomic neuropathy (HSAN) if sensory deficits and/or autonomic dysfunctions predominate (Dyck et al., 1993; Barisic et al., 2008; herein incorporated by reference in their entireties). HMSN or CMT is associated with more than 30 loci and at least 20 causative genes (see web sites for molgen.ua.ac.be/CMTMutations/; and neuro.wustl.edu/neuromuscular/time/hmsn.html; herein incorporated by reference in their entireties). Two kindreds were described with an autosomal dominant inherited disorder characterized by a variable degree of muscle weakness of limbs, vocal cords, and intercostal muscles and by asymptomatic sensory impairment in some cases (Dyck et al., 1994; herein incorporated by reference in its entirety). Life expectancy in the patients was shortened because of respiratory failure or complications. Because nerve conduction velocities were normal and the disorder represented an inherited axonal neuropathy, this condition was classified as a form of HMSN type II. Linkage analysis using the large Kinship 1, an American kindred of English and Scottish descent, excluded the loci of CMT1A (HMSN IA) and the CMT1B (HMSN IB) in this pedigree (Dyck et al., 1994; herein incorporated by reference in its entirety). This new form of autosomal dominant HMSN was assigned as HMSN IIC or CMT2C. The relationship of Kinship 1 was reexamined and 5 additional affected members were identified (Klein et al., 2003; herein incorporated by reference in its entirety). Using a genome wide scan approach and linkage analysis, it was established the locus of the HMSN IIC, or CMT2C to a 5.7 Mb region between D12S105 and D12S1330, with a lod score of 5.17 (Klein et al., 2003; herein incorporated by reference in its entirety). Subsequently, the CMT2C locus was further refined to a 4 Mb region between S12S105 and S12S1340, with a combined lod score of 2.1 using two relatively small families (McEntagart et al., 2005; herein incorporated by reference in its entirety).
The diagnosis of SPSMA and CMT2C is made qualitatively based on an assessment of clinical, electrophysiological and/or pathological features, transmission patterns, and age of a disease onset. What is needed is a molecular genetics tool available for a definitive diagnosis.